Cephem compounds and pharmaceutically acceptable salts thereof

ABSTRACT

The invention relates to a compound of the formula: ##STR1## of antimicrobial activity.

This is a continuation of application Ser. No. 07/714.995, filed on Jun.14, 1991, Now U.S. Pat. No. 5,173,485 which is a continuation of Ser.No. 07/317.981, filed on Mar. 2, 1989, now abandoned.

The present invention relates to new cephem compounds andpharmaceutically acceptable salts thereof.

More particularly, it relates to new cephem compounds andpharmaceutically acceptable salts thereof, which have antimicrobialactivities, to processes for preparation thereof, to pharmaceuticalcomposition comprising the same, and to a method for treating infectiousdiseases in human being and animals.

Accordingly, one object of the present invention is to provide thecephem compounds and pharmaceutically acceptable salts thereof, whichare highly active against a number of pathogenic microorganisms.

Another object of the present invention is to provide processes for thepreparation of the cephem compounds and salts thereof.

A further object of the present invention is to provide pharmaceuticalcomposition comprising, as an active ingredient, said cephem compoundsor their pharmaceutically acceptable salts.

Still further object of the present invention is to provide a method fortreating infectious diseases caused by pathogenic microorganisms, whichcomprises administering said cephem compounds to infected human being oranimals.

The object cephem compounds of the present invention are novel and canbe represented by the following general formula (I): ##STR2## wherein R¹is amino or a protected amino group,

R² is an organic group,

R³ is hydrogen, lower alkyl, hydroxy(lower)alkyl, protectedhydroxy(lower)alkyl, amino(lower)alkyl, protected amino(lower)alkyl oran imino protective group,

R⁴ is hydrogen, lower alkyl or lower alkylthio,

A is lower alkylene which may be substituted with suitablesubstituent(s), and

Z is N or CH.

The cephem compound (I) of the present invention can be prepared byprocesses as illustrated in the following. ##STR3## wherein R¹, R², R³,R⁴, A and Z are each as defined above,

R_(a) ¹ is a protected amino group,

R_(a) ² is protected carboxy(lower)alkyl,

R_(b) ² is carboxy(lower)alkyl,

R_(a) ³ is protected amino(lower)alkyl and

R_(b) ³ is amino(lower)alkyl.

The starting compound (II) is novel and can be prepared by processes asillustrated in the following. ##STR4## wherein R³, R⁴ and A are each asdefined above,

X is an acid residue,

R⁵ is a protected amino group,

R⁶ is a protected carboxy group,

Y is an acid residue, and

R_(c) ³ is an imino protective group.

Further, the compound (V) or a salt thereof can be prepared also by themethods disclosed in the Preparations described later or similar mannersthereto.

Regarding the compounds (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) and(III), it is to be understood that said compounds include syn isomer,anti isomer and a mixture thereof. For example, with regard to theobject compound (I), syn isomer means one geometrical isomer having thepartial structure represented by the following formula: ##STR5##(wherein R¹, R² and Z are each as defined above) and anti isomer meansthe other geometrical isomer having the partial structure represented bythe following formula: ##STR6## (wherein R¹, R² and Z are each asdefined above).

Regarding the other compounds, as mentioned above, the syn isomer andthe anti isomer can also be referred to the same geometrical isomers asillustrated for the compound (I).

Suitable pharmaceutically acceptable salts of the object compound (I)are conventional non-toxic salt and include a metal salt such as analkali metal salt (e.g. sodium salt, potassium salt, etc.) and analkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), anammonium salt, an organic base salt (e.g. trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt(e.g. acetate, trifluoroacetate, maleate, tartrate, methanesulfonate,benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acidsalt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate,etc.), or a salt with an amino acid (e.g. arginine, aspartic acid,glutamic acid, etc.), and the like.

In the above and subsequent descriptions of the present specification,suitable examples and illustrations of the various definitions which thepresent invention include within the scope thereof are explained indetail as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s) unlessotherwise indicated.

Suitable "protected amino" and "protected amino moiety" in the term"protected amino(lower)alkyl" may include an acylamino or an amino groupsubstituted by a conventional protective group such as ar(lower)alkylwhich may have suitable substituent(s) (e.g. benzyl, trityl, etc.) orthe like.

Suitable "acyl moiety" in the term "acylamino" may include carbamoyl,aliphatic acyl group and acyl group containing an aromatic orheterocyclic ring. And, suitable examples of the said acyl may be loweralkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl(e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.);

lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl,isopropanesulfonyl, butanesulfonyl, etc.); arenesulfonyl (e.g.benzenesulfonyl, tosyl, etc.);

aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl,indancarbonyl, etc.);

ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, etc.);

ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl,etc.), and the like. The acyl moiety as stated above may have suitablesubstituent(s) such as halogen (e.g. chlorine, bromine, iodine orfluorine) or the like.

Suitable "organic group" may include lower alkyl,

mono(or di or tri)halo(lower)alkyl (e.g. chloromethyl, dichloromethyl,trichloromethyl, bromomethyl, chloroethyl, dichloroethyl,trichloroethyl, fluoroethyl, trifluoroethyl, etc.),

lower alkenyl (e.g., vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or3 butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl,etc.),

lower alkynyl (e.g., ethynyl, 1-propynyl, propargyl, 1-methylpropargyl,1 or 2 or 3 butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or5-hexynyl, etc.),

aryl (e.g., phenyl, naphthyl, etc.),

ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl, phenethyl,phenylpropyl, etc.),

carboxy(lower)alkyl, protected carboxy(lower)alkyl, and the like.

Suitable "protected carboxy" and "protected carboxy moiety" in the term"protected carboxy(lower)alkyl" may include esterified carboxy and thelike. And suitable examples of said ester may be the ones such as

lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester,isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentylester, t-pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.);

lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.);

lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.);

lower alkoxyalkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester,isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester,etc.);

lower alkylthioalkyl ester (e.g., methylthiomethyl ester,ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester,etc.);

mono(or di or tri)-halo(lower)alkyl ester (e.g. 2-iodoethyl ester,2,2,2-trichloroethyl ester, etc.);

lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester,propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethylester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethylester, 2-propionyloxyethyl ester, etc.);

lower alkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester,2-mesylethyl ester etc.);

ar(lower)alkyl ester, for example, phenyl(lower)alkyl ester which mayhave one or more suitable substituent(s) (e.g., benzyl ester,4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, tritylester, benzhydryl ester, bis(methoxyphenyl)methyl ester,3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.);

aryl ester which may have one or more suitable substituent(s) such assubstituted or unsubstituted phenyl ester (e.g. phenyl ester, tolylester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester,4-chlorophenyl ester, 4-methoxyphenyl ester, etc.);

tri(lower)alkyl silyl ester;

lower alkylthioester (e.g. methylthioester, ethylthioester, etc.) andthe like.

Suitable "lower alkyl" and "lower alkyl moiety" in the terms"hydroxy(lower)alkyl", "protected hydroxy(lower)alkyl", "loweralkylthio", "carboxy(lower)alkyl", "protected carboxy(lower)alkyl","amino(lower)alkyl" and "protected amino(lower)alkyl" may includestraight or branched one such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, hexyl or the like.

Suitable "hydroxy protective group" in the term "protectedhydroxy(lower)alkyl" may include an acyl group as exemplified above, andthe like.

Suitable "imino protective group" may include an acyl group asexemplified above, and the like.

suitable "lower alkylene" may include methylene, ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene and the like.

Suitable "substituent" in the term "lower alkylene which may besubstituted with suitable substituent(s)" may include oxo, hydroxy,protected hydroxy wherein hydroxy protective group can be referred tothe ones as exemplified above, and the like.

Suitable "acid residue" may include halogen [e.g. chlorine, bromine,iodine, etc.], acyloxy such as sulfonyloxy [e.g. benzenesulfonyloxy,tosyloxy, mesyloxy, etc.], lower alkanoyloxy [e.g. acetyloxy,propionyloxy, etc.] or the like.

Preferred embodiments of the object compound (I) are as follows.

R¹ is amino or acylamino (more preferably lower alkanoylamino),

R² is lower alkyl, lower alkenyl, carboxy(lower)alkyl or protectedcarboxy(lower)alkyl [more preferably esterified carboxy(lower)alkyl,most preferably lower alkoxycarbonyl(lower)alkyl],

R³ is hydrogen, lower alkyl, hydroxy(lower)alkyl, amino(lower)alkyl,protected amino(lower)alkyl [more preferably acylamino(lower)alkyl, mostpreferably lower alkanoylamino(lower)alkyl] or an imino protective group(more preferably an acyl group, most preferably lower alkanoyl),

R⁴ is hydrogen, lower alkyl or lower alkylthio,

A is lower alkylene which may be substituted with an oxo or a hydroxygroup [more preferably C₂ -C₃)alkylene which may be substituted with anoxo or a hydroxy group, most preferably ethylene, trimethylene, ortrimethylene substituted with an oxo or a hydroxy group], and

Z is N or CH.

The processes for preparing the object compounds of the presentinvention are explained in detail in the following.

Process 1

The compound (I) or a salt thereof can be prepared by reacting thecompound (II) or its reactive derivative at the amino group or a saltthereof with the compound (III) or its reactive derivative at thecarboxy group or a salt thereof.

Suitable reactive derivative at the amino group of the compound (II) mayinclude Schiff's base type imino or its tautomeric enamine type isomerformed by the reaction of the compound (II) with a carbonyl compoundsuch as aldehyde, ketone or the like; a silyl derivative formed by thereaction of the compound (II) with a silyl compound such asbis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide [e.g.N-(trimethylsilyl)acetamide], bis(trimethylsilyl)urea or the like;

a derivative formed by reaction of the compound (II) with phosphorustrichloride or phosgene, and the like.

Suitable salts of the compound (II) and its reactive derivative can bereferred to the ones as exemplified for the compound (I).

Suitable reactive derivative at the carboxy group of the compound (III)may include an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like. Suitable examples of the reactivederivatives may be an acid chloride; an acid azide;

a mixed acid anhydride with an acid such as substituted phosphoric acid[e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoricacid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.],dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuricacid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphaticcarboxylic acid [e.g. acetic acid, propionic acid, butyric acid,isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylicacid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride;

an activated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole or tetrazole;

or an activated ester [e.g. cyanomethyl ester, methoxymethyl ester,dimethyliminomethyl [(CH₃)₂ N═CH--] ester, vinyl ester, propargyl ester,p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester,pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester,phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester,8-quinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g.N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole,etc.], and the like. These reactive derivatives can optionally beselected from them according to the kind of the compound (III) to beused.

Suitable salts of the compound (III) and its reactive derivative can bereferred to the ones as exemplified for the compound (I).

The reaction is usually carried out in a conventional solvent such aswater, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvent may also be used in a mixture with water.

In this reaction, when the compound (III) is used in a free acid form orits salt form, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;

N-cyclohexyl-N'-morpholinoethylcarbodiimide;

N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;

N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide;

N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;

N,N'-carbonylbis-(2-methylimidazole);

pentamethyleneketene-N-cyclohexylimine;

diphenylketene-N-cyclohexylimine; ethoxyacetylene;

1-alkoxy-1-chloroethylene; trialkyl phosphite;

ethyl polyphosphate;

isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);

phosphorus trichloride; thionyl chloride;

oxalyl chloride;

lower alkyl haloformate [e.g. ethyl chloroformate, isopropylchloroformate, etc.];

triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;

2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;

1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, trichloromethyl chloroformate, phosphorusoxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic ororganic base such as an alkali metal bicarbonate, tri(lower)alkylamine,pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, orthe like.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to warming.

Process 2

The compound (Ib) or a salt thereof can be prepared by subjecting thecompound (Ia) or a salt thereof to elimination reaction of the aminoprotective group. Suitable method of this elimination reaction mayinclude conventional one such as hydrolysis, reduction and the like.

Suitable salts of the compounds (Ia) and (Ib) can be referred to theones as exemplified for the compound (I).

(i) For Hydrolysis:

The hydrolysis is preferably carried out in the presence of a base or anacid including Lewis acid.

Suitable base may include an inorganic base and an organic base such asan alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal[e.g. magnesium, calcium, etc.], the hydroxide or carbonate orbicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine,etc.], picoline, 1,5-diazabicyclo[4.3.0]-non-5-ene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, orthe like.

Suitable acid may include an organic acid [e.g. formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.]and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid,sulfuric acid, hydrogen chloride, hydrogen bromide, etc.]. Theelimination using Lewis acid such as trihaloacetic acid [e.g.trichloroacetic acid, trifluoroacetic acid, etc.] or the like ispreferably carried out in the presence of cation trapping agents [e.g.anisole, phenol, etc.].

The reaction is usually carried out in a solvent such as water, analcohol [e.g. methanol, ethanol, etc.], methylene chloride,tetrahydrofuran, a mixture thereof or any other solvent which does notadversely influence the reaction. A liquid base or acid can be also usedas the solvent. The reaction temperature is not critical and thereaction is usually carried out under cooling to warming.

(ii) For reduction:

Reduction is carried out in a conventional manner, including chemicalreduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound(e.g. chromium chloride, chromium acetate, etc.) and an organic orinorganic acid (e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.).

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalysts (e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.), palladium catalysts (e.g. spongy palladium palladium black,palladium oxide, palladium on carbon, colloidal palladium palladium onbarium sulfate, palladium on barium carbonate, etc.), nickel catalysts(e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobaltcatalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts(e.g. reduced iron, Raney iron, etc.), copper catalysts (e.g. reducedcopper, Raney copper, Ullman copper, etc.) and the like. The reductionis usually carried out in a conventional solvent which does notadversely influence the reaction such as water, methanol, ethanol,propanol, N,N-dimethylformamide, or a mixture thereof. Additionally, incase that the above-mentioned acids to be used in chemical reduction arein liquid, they can also be used as a solvent. Further, a suitablesolvent to be used in catalytic reduction may be the above-mentionedsolvent, and other conventional solvent such as diethyl ether, dioxane,tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature of this reduction is not critical and thereaction is usually carried out under cooling to warming.

Process 3

The compound (Id) or a salt thereof can be prepared by subjecting thecompound (Ic) or a salt thereof to elimination reaction of the carboxyprotective group.

Suitable salts of the compounds (Ic) and (Id) can be referred to theones as exemplified for the compound (I).

This reaction can be carried out in a similar manner to that of theaforementioned Process 2, and therefore the reagents to be used and thereaction conditions (e.g., solvent, reaction temperature, etc.) can bereferred to those of the Process 2.

Process 4

The compound (If) or a salt thereof can be prepared by subjecting thecompound (Ie) or a salt thereof to elimination reaction of the aminoprotective group.

Suitable salts of the compounds (Ie) and (If) can be referred to theones as exemplified for the compound (I).

This reaction can be carried out in a similar manner to that of theaforementioned Process 2, and therefore the reagents to be used and thereaction conditions (e.g., solvent, reaction temperature, etc.) can bereferred to those of the Process 2.

The processes for preparing the starting compounds are explained in thefollowing.

Process A

The compound (V) or a salt thereof can be prepared by subjecting thecompound (IV) or a salt thereof to cyclization reaction. This reactioncan be referred to that of Preparation 1(3) as mentioned below.

Process B-○1

The compound (VII) or a salt thereof can be prepared by reacting thecompound (VI) or a salt thereof with the compound (V) or a salt thereof.

The present reaction may be carried out in a solvent such as water,phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene,methylene chloride, ethylene chloride, formamide, N,N-dimethylformamide,methanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide,or any other organic solvent which does not adversely affect thereaction. The reaction temperature is not critical, and the reaction isusually carried out at ambient temperature, under warming or underheating.

Process B-○2

The compound (II) or a salt thereof can be prepared by subjecting thecompound (VII) or a salt thereof to elimination reaction of the aminoprotective group in R⁵ and the carboxy protective group in R⁶. Thisreaction can be carried out in a similar manner to that of theaforementioned Process 2, and therefore the reagents to be used and thereaction conditions (e.g., solvent, reaction temperature, etc.) can bereferred to those of the Process 2.

Process C

The compound (IIb) or a salt thereof can be prepared by subjecting thecompound (IIa) or a salt thereof to elimination reaction of the iminoprotective group. This reaction can be carried out in a similar mannerto that of the aforementioned Process 2, and therefore the reagents tobe used and the reaction conditions (e.g., solvent, reactiontemperature, etc.) can be referred to those of the Process 2.

The present invention includes within the scope of the invention thecase that protected hydroxy in "A" is transformed into hydroxy duringthis reaction.

The object compound (I) and pharmaceutically acceptable salts thereofare novel and exhibit high antimicrobial activity, inhibiting the growthof a wide variety of pathogenic microorganisms including Gram-positiveand Gram-negative microorganisms and are useful as antimicrobial agents.

Now in order to show the utility of the object compound (I), the testdata on MIC (minimal inhibitory concentration) of a representativecompound of the compound (I) are shown in the following.

Test method:

In vitro antibacterial activity was determined by the two-foldagar-plate dilution method as described below.

One loopful of an overnight culture of each test strain inTrypticase-soy broth (10⁸ viable cells per ml) was streaked on heartinfusion agar (HI-agar) containing graded concentrations ofrepresentative test compound, and the minimal inhibitory concentration(MIC) was expressed in terms of μg/ml after incubation at 37° C. for 20hours.

Test compound:

(1)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylate(syn isomer)

Test result:

    ______________________________________                                        MIC (μg/ml)                                                                Test strain  Test Compound (1)                                                ______________________________________                                        E. coli 31   ≦0.025                                                    ______________________________________                                    

For therapeutic administration, the object compound (I) andpharmaceutically acceptable salts thereof of the present invention areused in the form of conventional pharmaceutical preparation whichcontains said compound as an active ingredient, in admixture withpharmaceutically acceptable carriers such as an organic or inorganicsolid or liquid excipient which is suitable for oral, parenteral andexternal administration. The pharmaceutical preparations may be in solidform such as tablet, granule, powder, capsule, or liquid form such assolution, suspension, syrup, emulsion, lemonade and the like.

If needed, there may be included in the above preparations auxiliarysubstances, stabilizing agents, wetting agents and other commonly usedadditives such as lactose, citric acid, tartaric acid, stearic acid,magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin,agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, andthe like.

While the dosage of the compound (I) may vary from and also depend uponthe age, conditions of the patient, a kind of diseases, a kind of thecompound (I) to be applied, etc., in general, amounts between 1 mg andabout 4,000 mg or even more per day may be administered to a patient. Anaverage single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, ofthe object compound (I) of the present invention may be used in treatingdiseases infected by pathogenic microorganisms.

The following Preparations and Examples are given for the purpose ofillustrating the present invention in more detail.

Preparation 1

(1) A mixture of acetic anhydride (44.5 ml) and formic acid (22.3 ml)was stirred at ambient temperature for an hour. To this mixture wasadded 1-(2-hydroxyethyl)-5-aminopyrazole (30 g) at 0°-10° C., and themixture was stirred under ice-cooling for 30 minutes. The mixture waspoured into ice-cold water, adjusted to pH 10.5 with 40% aqueouspotassium carbonate, and stirred under ice-cooling for 30 minutes. Themixture was extracted with a mixture of tetrahydrofuran and ethylacetate 6 times. The organic layer was dried over magnesium sulfate andevaporated in vacuo to give 1-(2-hydroxyethyl)-5-formamidopyrazole (30.8g).

IR (Nujol): 3230, 1695, 1570, 1540 cm⁻¹ NMR (DMSO-d₆, δ): 3.62-3.95 (2H,m), 3.98-4.32 (2H, m), 6.22 and 6.36 (1H, each d, J=3 Hz), 7.42 (1H, d,J=3 Hz), 8.32 and 8.36 (1H, each s)

(2) To a solution of 1-(2-hydroxyethyl)-5-formamidopyrazole (10 g) andtriethylamine (18 ml) in methylene chloride (100 ml) was added dropwisemethanesulfonyl chloride (8.5 ml) under ice-cooling. The mixture wasstirred at 0° C. for 1.5 hours. The reaction mixture was poured intowater (20 ml) and the methylene chloride layer was separated. Theaqueous layer was reextracted with tetrahydrofuran twice. The organiclayers were combined and dried over magnesium sulfate. The solvent wasevaporated and the residue was subjected to column chromatography onsilica gel (200 g) using ethyl acetate as an eluent. Fractionscontaining the object compound were combined and evaporated in vacuo togive 1-(2-methylsulfonyloxyethyl)-5-formamidopyrazole (3.2 g) ascrystals.

mp: 101°-104° C. IR (Nujol): 3300, 1780, 1730, 1660-1680, 1540-1560 cm⁻¹NMR (DMSO-d₆, δ): 2.93 (3H, s), 4.18-4.60 (4H, m), 6.08-6.40 (1H, m),7.33 (1H, d, J=2 Hz), 8.17-8.43 (1H, m), 9.97-10.63 (1H, m)

(3) To a solution of 1-(2-methylsulfonyloxyethyl)-5-formamidopyrazole(6.2 g) in N,N-dimethylformamide (60 ml) was added 62% sodium hydride(1.03 g) under ice-cooling. The mixture was stirred at the samecondition for 3 hours. The reaction mixture was poured into ethylacetate (300 ml) and the insoluble material was filtered off. Thefiltrate was evaporated under reduced pressure and the residue wassubjected to column chromatography on silica gel (100 g) using a mixtureof diisopropyl ether and ethyl acetate as an eluent. Fractionscontaining the object compound were combined and evaporated in vacuo togive 1-formyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (3.91 g) ascrystals.

mp: 78°-80° C. IR (Nujol): 1650, 1570, 1520 cm⁻¹ NMR (CDCl₃, δ):4.10-4.70 (4H, m), 5.77 (1H, d, J=2 Hz), 7.37 (1H, d, J=2 Hz), 8.61 (1H,s)

Preparation 2

(1) To a suspension of 5-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(0.5 g) in tetrahydrofuran (10 ml) was added lithium aluminum hydride(0.277 g) at room temperature. The mixture was stirred at ambienttemperature for 30 minutes. To the mixture was added sodium fluoride(1.22 g), and then water (0.394 g) was added dropwise thereto underice-cooling. The mixture was stirred at 0°-5° C. for 30 minutes andfiltered. The filtrate was evaporated to give4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (257 mg).

IR (Nujol): 3220, 1570, 1460 cm⁻¹ NMR (DMSO-d₆, δ): 1.78-2.01 (2H, m),3.0-3.21 (2H, m), 3.90 (2H, t, J=6 Hz), 5.10 (1H, d, J=2 Hz), 5.86 (1H,br s), 6.97 (1H, d, J=2 Hz)

(2) To acetic anhydride (0.153 ml) was added formic acid (0.077 ml) at15°-20° C. The mixture was stirred at ambient temperature for 30minutes. To this solution was added4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (100 mg) under ice-coolingand the mixture was stirred at the same temperature for 1 hour. Thereaction mixture was added to a mixture of dichloromethane and aqueoussodium bicarbonate solution. The separated organic layer was dried overmagnesium sulfate and evaporated in vacuo to give4-formyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (79.9 mg).

IR (Nujol): 1670, 1535, 1500, 1450, 1430, 1400 cm⁻¹ NMR (DMSO-d₆, δ):1.97-2.27 (2H, m), 3.62-3.91 (2H, m), 3.97-4.24 (2H, m), 6.22 and 6.48(1H, each d, J=3 Hz), 7.29 (1H, d, J=3 Hz), 8.19 and 8.77 (1H, each s)

Preparation 3

(1) To a solution of 1-(2-hydroxyethyl)-4-ethoxycarbonyl-5-aminopyrazole(200 g) in a mixture of methylene chloride (2 l) and triethylamine (210ml) was added dropwise methanesulfonyl chloride (85.5 ml) underice-cooling. The mixture was stirred for 1 hour at 3°-5° C. The reactionmixture was poured into ice-water (700 ml). The separated organic layerwas washed with 1N hydrochloric acid and water, and dried over magnesiumsulfate. The solvent was evaporated to give1-(2-methylsulfonyloxyethyl)-4-ethoxycarbonyl-5-aminopyrazole (270.8 g)as crystals.

IR (Nujol): 3450, 3340, 1680, 1625, 1540 cm⁻¹ NMR (DMSO-d₆, δ): 1.20(3H, t, J=7 Hz), 3.04 (3H, s), 4.03-4.57 (6H, m), 6.28 (2H, br s), 7.47(1H, s)

(2) A mixture of acetic anhydride (184 ml) and formic acid (93 ml) wasstirred for 30 minutes at room temperature. The mixture was cooled at 5°C. with ice-bath and added to1-(2-methylsulfonyloxyethyl)-4-ethoxycarbonyl-5-aminopyrazole (270 g).The mixture was stirred for 3 hours under ice-cooling. The reactionmixture was evaporated to give crystals. To the crystals was addeddiisopropyl ether and the mixture was stirred for 1 hour. The crystalswere collected by filtration to give1-(2-methylsulfonyloxyethyl)-4-ethoxycarbonyl-5-formamidopyrazole (291.5g).

IR (Nujol): 3250, 1720, 1670, 1570, 1530 cm⁻¹ NMR (DMSO-d₆, δ): 1.25(3H, t, J=7 Hz), 3.10 (3H, s), 4.00-4.60 (6H, m), 7.86 (1H, s), 8.24(1H, br s)

(3) 1-Formyl-2,3-dihydro-7-ethoxycarbonyl-1H-imidazo-[1,2-b]pyrazole wasobtained according to a similar manner to that of Preparation 1(3).

IR (Nujol): 1670-1710, 1580, 1520 cm⁻¹ NMR (DMSO-d₆, δ): 1.25 (3H, t,J=7 Hz), 4.02-4.60 (6H, m), 7.67 (1H, s), 9.46 (1H, s)

(4) To a suspension of1-formyl-2,3-dihydro-7-ethoxycarbonyl-1H-imidazo[1,2-b]pyrazole (40 g)in methanol (200 ml) was added conc. hydrochloric acid (31.9 ml) underice-cooling. The mixture was stirred at room temperature for 2 hours.The reaction mixture was poured into ice-water (300 ml) and adjusted topH 6.5 with 40% aqueous potassium carbonate solution. The mixture wasevaporated to precipitate the crystals. The crystals were collected byfiltration to give2,3-dihydro-7-ethoxycarbonyl-1H-imidazo[1,2-b]pyrazole (33.4 g).

NMR (DMSO-d₆, δ): 1.20 (3H, t, J=7 Hz), 3.70-4.27 (6H, m), 6.46 (1H, brs), 7.40 (1H, s)

(5) To a solution of2,3-dihydro-7-ethoxycarbonyl-1H-imidazo[1,2-b]pyrazole (5 g) in xylene(27 ml) was added dropwise 3.4M solution (27 ml) of sodiumbis(2-methoxyethoxy)aluminum hydride in toluene under ice-cooling. Themixture was stirred at room temperature and then stirred at 140° C. for3.5 hours. The reaction mixture was cooled at 5° C. and poured into amixture of ice-water (100 ml) and tetrahydrofuran (100 ml). Theinsoluble material was filtered off and the filtrate was separated. Theaqueous layer was extracted with tetrahydrofuran. The organic layer andextract were combined and dried over magnesium sulfate. The solvent wasevaporated to give 2,3-dihydro-7-methyl-1H-imidazo[1,2-b]pyrazole (2.04g).

NMR (DMSO-d₆, δ): 1.85 (3H, s), 3.57-4.10 (4H, m), 5.37 (1H, br s), 6.97(1H, s)

(6) 1-Formyl-2,3-dihydro-7-methyl-1H-imidazo[1,2-b]pyrazole was obtainedaccording to a similar manner to that of Preparation 2(2).

NMR (DMSO-d₆, δ): 2.09 (3H, s), 4.05-4.70 (4H, m), 7.17 (1H, s), 8.70(1H, s)

Preparation 4

(1) To a solution of 2,3-dihydro-1H-imidazo[1,2-b]-pyrazole (19 g) indimethylsulfoxide (95 ml) were added ethyl bromoacetate (20.4 ml) andpotassium bicarbonate (30 g) under ice-cooling. The mixture was stirredat room temperature for 4 hours. The reaction mixture was poured into amixture of ethyl acetate (1.5 l) and water (500 ml). The separatedorganic layer was washed with water and brine, and dried over magnesiumsulfate. The solvent was evaporated and the residue was subjected tocolumn chromatography on silica gel using ethyl acetate as an eluent.Fractions containing the object compound were combined and evaporated invacuo to give1-ethoxycarbonylmethyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (20.3 g).

IR (Nujol): 3400, 1710-1760, 1570 cm⁻¹ NMR (DMSO-d₆, δ): 1.13 (3H, t,J=7 Hz), 3.63-4.30 (6H, m), 4.27 (2H, s), 5.20 (1H, s), 7.07 (1H, s)

(2) To a suspension of lithium aluminum hydride (3.89 g) intetrahydrofuran (195 ml) was added dropwise a solution of1-ethoxycarbonylmethyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (20 g) intetrahydrofuran (100 ml) at room temperature. The mixture was stirred at50° C. for 1 hour. The reaction mixture was cooled under ice-bath. To amixture were added sodium fluoride (17.2 g) and water (5.5 ml) underice-cooling. The insoluble material was filtered off and the filtratewas evaporated. The residue was subjected to column chromatography onsilica gel using ethyl acetate as an eluent. Fractions containing theobject compound were combined and evaporated in vacuo to give1-(2-hydroxyethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (5.91 g).

IR (Nujol): 3250-3350, 1560-1570, 1505 cm⁻¹ NMR (DMSO-d₆, δ): 3.04 (2H,t, J=5 Hz), 3.43-3.57 (2H, m), 3.57-4.17 (4H, m), 4.69 (1H, t, J=5 Hz),5.27 (1H, d, J=3 Hz), 7.15 (1H, d, J=3 Hz)

Preparation 5

To a suspension of 62% sodium hydride (1.41 g) in N,N-dimethylformamide(30 ml) was added 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (4.5 g)under ice-cooling. To this solution was added dropwise methyl iodide(2.27 ml) under ice-cooling, and the mixture was stirred at the sametemperature for 1.5 hours. The reaction mixture was poured into ethylacetate (50 ml), and the resulting precipitate was filtered off. Thefiltrate was evaporated to give4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (5.05 g).

NMR (CDCl₃, δ): 2.08-2.32 (2H, m), 3.01-3.13 (2H, m), 4.03-4.22 (2H, m),5.29 (1H, d, J=3 Hz), 7.22 (1H, d, J=3 Hz)

Preparation 6

The following compound was obtained according to a similar manner tothat of Preparation 5.

1-Methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole

NMR (CDCl₃, δ): 2.83 (3H, s), 3.52-3.82 (2H, m), 3.93-4.30 (2H, m), 5.29(1H, d, J=3 Hz), 7.31 (1H, d, J=3 Hz)

Preparation 7

To a solution of benzhydryl7β-t-butoxycarbonylamino-3-chloromethyl-4-carboxylate (5.76 g) inN,N-dimethylformamide (5.8 ml) was added sodium iodide (1.68 g). Afterthe mixture was stirred at room temperature for 30 minutes,1-formyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (4.6 g) was addedthereto. The mixture was stirred at room temperature overnight. Thereaction mixture was poured into a mixture of ice water (30 ml) andethyl acetate (120 ml). The separated organic layer was washed withwater and then brine, and dried over magnesium sulfate. The solvent wasdistilled off and the residue was pulverized with diisopropyl ether andcollected by filtration to give benzhydryl7β-t-butoxycarbonylamino-3-[1-formyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide (7.52 g).

NMR (DMSO-d₆, δ): 1.35 (9H, s), 3.47 (2H, br s), 4.07-4.80 (4H, m), 5.12(1H, d, J=5 Hz), 5.27 (2H, br s), 5.52, 5.62 (1H, dd, J=5 Hz, 8 Hz),6.47-6.73 (1H, m), 6.87 (1H, s), 7.02-7.57 (10H, m), 7.60-8.08 (1H, m),8.25 (1H, d, J=3 Hz), 8.09 (1H, s)

Preparation 8

The following compounds were obtained according to a similar manner tothat of Preparation 7.

(1) Benzhydryl7β-t-butoxycarbonylamino-3-(4-methyl-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylateiodide

IR (Nujol): 3300, 1775, 1705, 1615 cm⁻¹ NMR (DMSO-d₆, δ): 1.44 (9H, s),1.82-2.22 (2H, m), 2.99 (3H, s), 3.23-4.07 (6H, m), 5.08-5.22 (3H, m),5.55 (1H, dd, J=8, 5 Hz), 6.13 (1H, d, J=3 Hz), 6.93 (1H, s), 7.13-7.51(10H, m), 7.85 (1H, d, J=8 Hz), 8.02 (1H, d, J=3 Hz)

(2) Benzhydryl7β-t-butoxycarbonylamino-3-(4-formyl-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylateiodide

IR (Nujol): 1785, 1705, 1560 cm⁻¹ NMR (DMSO-d₆, δ): 1.43 (9H, s),1.88-2.27 (2H, m), 3.46 (2H, br s), 3.55-4.22 (4H, m), 5.15 (1H, d, J=5Hz), 5.43 (2H, br s), 5.58 (1H, dd, J=8 Hz, 5 Hz), 6.91 (1H, s), 7.01(1H, d, J=3 Hz), 7.13-7.55 (10H, m), 7.94 (1H, d, J=8 Hz), 8.32 (1H, d,J=3 Hz), 8.43 and 9.04 (1H, each s)

(3) Benzhydryl7β-t-butoxycarbonylamino-3-(5-oxo-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylateiodide

IR (Nujol): 1780, 1710, 1590 cm⁻¹ NMR (DMSO-d₆, δ): 1.43 (9H, s), 2.76(2H, t, J=8 Hz), 3.43 (2H, br s), 4.13 (2H, J=8 Hz), 5.12 (1H, d, J=5Hz), 5.38 (2H, br s), 5.58 (1H, dd, J=8, 5 Hz), 6.18 (1H, d, J=3 Hz),6.91 (1H, s), 7.12-7.53 (10H, m), 7.93 (1H, d, J=8 Hz), 8.25 (1H, d, J=3Hz)

(4) Benzhydryl7β-t-butoxycarbonylamino-3-[1-(2-hydroxyethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

IR (Nujol): 3400, 1780, 1670 cm⁻¹ NMR (DMSO-d₆, δ): 3.40-4.00 (4H, m),4.07-4.70 (4H, m), 5.01-5.50 (4H, m), 5.20 (1H, d, J=5 Hz), 5.60 (1H,dd, J=5 Hz, 8 Hz), 6.01 (1H, d, J=3 Hz), 6.90 (1H, s), 7.02-7.49 (10H,m), 8.10 (1H, d, J=3 Hz)

(5) Benzhydryl7β-t-butoxycarbonylamino-3-[1-formyl-2,3-dihydro-7-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

NMR (DMSO-d₆, δ): 1.43 (9H, s), 2.20 (3H, s), 3.22 (2H, br s), 4.07-4.80(4H, m), 5.03-5.37 (3H, m), 5.63 (1H, dd, J=5 Hz, 8 Hz), 6.94 (1H, s),7.10-7.63 (10H, m), 8.15 (1H, s), 8.90 (1H, br s)

(6) Benzhydryl7β-t-butoxycarbonylamino-3-[1-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

NMR (DMSO-d₆, δ): 1.38 (9H, s), 2.90 (3H, s), 3.30-3.67 (2H, m),3.72-4.10 (4H, m), 4.90-5.10 (2H, m), 5.13 (1H, d, J=5 Hz), 5.54 (1H,dd, J=5 Hz, 8 Hz), 6.02 (1H, d, J=3 Hz), 6.89 (1H, s), 7.07-7.53 (10H,m), 8.05 (1H, d, J=3 Hz)

(7) Benzhydryl7β-t-butoxycarbonylamino-3-(4-formyl-6-formyloxy-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)-methyl-3-cephem-4-carboxylateiodide

IR (Nujol): 1780, 1710 cm⁻¹ NMR (DMSO-d₆, δ): 1.43 (9H, s), 3.2-3.8 (3H,m), 4.1-4.6 (2H, m), 5.14 (1H, d, J=5 Hz), 5.40 (2H, s), 5.60 (1H, dd,J=8 Hz, 5 Hz), 6.86 (1H, s), 7.06 (1H, d, J=3 Hz), 7.2-7.6 (10H, m),7.93 (1H, d, J=8 Hz), 8.17 (1H, d, J=3 Hz), 8.20 (1H, s), 8.86 (1H, s)

(8) Benzhydryl7β-t-butoxycarbonylamino-3-[1-(2-formamidoethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide

IR (Nujol): 1780, 1710, 1670, 1610, 1520 cm⁻¹ NMR (DMSO-d₆, δ): 1.40(9H, s), 3.10-3.60 (6H, m), 3.82-4.17 (4H, m), 4.87-5.13 (2H, m), 5.16(1H, d, J=5 Hz), 5.58 (1H, dd, J=5 Hz, 8 Hz), 5.99 (1H, d, J=2 Hz), 6.93(1H, s), 7.10-7.53 (10H, m), 7.98 (1H, s), 8.07 (1H, d, J=2 Hz)

(9) Benzhydryl7β-t-butoxycarbonylamino-3-[1-formyl-7-methylthio-2,3-dihydro-5-(1H-imiazo[1,2-b]pyrazolio)]methyl-3-cephem-4-caroxylateiodide

IR (Nujol): 1780, 1670, 1510 cm⁻¹

Preparation 9

To a suspension of benzhydryl7β-t-butoxycarbonylamino-3-[1-formyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylateiodide (7.5 g) in a mixture of anisole and methylene chloride was addeddropwise trifluoroacetic acid (15 ml) under ice-cooling. The mixture wasstirred at room temperature for 1.5 hours. The reaction mixture waspoured into a mixture of diisopropyl ether (115 ml) and ethyl acetate(115 ml). The resultant powder was collected by filtration and washedwith diisopropyl ether and dried over phosphorus pentoxide in vacuo togive7β-amino-3-[1-formyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate) (6.6 g).

Preparation 10

The following compounds were obtained according to a similar manner tothat of Preparation 9.

(1)7β-Amino-3-(4-methyl-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

IR (Nujol): 1780, 1665, 1620 cm⁻¹ NMR (DMSO-d₆, δ): 1.84-2.29 (2H, m),3.03 (3H, m), 3.13-3.55 (4H, m), 3.82-4.22 (2H, m), 5.13-5.33 (4H, m),6.17 (1H, d, J=3 Hz), 8.05 (1H, d, J=3 Hz)

(2)7β-Amino-3-(4-formyl-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

IR (Nujol): 3350, 1780, 1650 cm⁻¹ NMR (DMSO-d₆, δ): 2.04-2.45 (2H, m),3.49 (2H, br s), 3.72-4.38 (4H, m), 5.22 (2H, br s), 5.49 (2H, br s),7.07 (1H, br s), 8.35 (1H, d, J=3 Hz), 8.47 and 9.07 (1H, each s)

(3)7β-Amino-3-(5-oxo-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

IR (Nujol): 1775, 1680, 1590 cm⁻¹ NMR (DMSO-d₆, δ): 2.99 (2H, t, J=7Hz), 3.46 (2H, br s), 4.43 (2H, t, J=7 Hz), 5.19 (2H, br s), 5.44 (2H,br s), 6.23 (1H, d, J=3 Hz), 8.27 (1H, J=3 Hz)

(4)7β-Amino-3-[1-(2-hydroxyethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

IR (Nujol): 3400, 1775, 1650, 1510 cm⁻¹ NMR (D₂ O, δ): 3.37-3.90 (4H,m), 3.97-4.53 (4H, m), 4.97-5.40 (4H, m), 5.91 (1H, d, J=3 Hz), 7.96(1H, d, J=3 Hz)

(5)7β-Amino-3-[1-formyl-2,3-dihydro-7-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

NMR (DMSO-d₆, δ): 2.20 (3H, s), 3.55 (2H, br s), 4.33-4.73 (4H, m),5.02-5.43 (4H, m), 8.20 (1H, s), 8.87 (1H, br s)

(6)7β-Amino-3-[1-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

NMR (D₂ O-NaHCO₃, δ): 2.87 (3H, s), 3.12, 3.40 (2H, ABq, J=18 Hz, 24Hz), 3.63-4.30 (4H, m), 4.73-5.10 (4H, m), 5.75 (1H, d, J=3 Hz), 7.82(1H, d, J=3 Hz)

(7)7β-Amino-3-(4-formyl-6-formyloxy-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

IR (Nujol): 1780, 1700 cm⁻¹ NMR (DMSO-d₆, δ): 3.52 (2H, br s), 3.2-3.8(3H, m), 4.1-4.6 (2H, m), 5.26 (2H, m), 5.52 (2H, s), 7.15 (1H, d, J=3Hz), 8.22(1H, d, J=3 Hz), 8.50 (1H, s), 9.20 (1H, s)

(8)7β-Amino-3-[1-(2-formamidoethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

NMR (D₂ O-NaHCO₃, δ): 3.17, 3.46 (2H, ABq, J=18 Hz, 26 Hz), 3.50 (4H,s), 3.95-4.50 (4H, m), 4.86, 5.03 (2H, ABq, J=11 Hz, 16 Hz), 5.06 (1H,d, J=5 Hz), 5.85 (1H, d, J=2 Hz), 7.92 (1H, d, J=2 Hz), 8.01 (1H, s)

(9)7β-Amino-3-[1-formyl-7-methylthio-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate)

NMR (D₂ O, δ): 2.29, 2.32 (total 3H, each s), 3.20-3.63 (2H, m),4.03-4.60 (4H, m), 4.87-5.45 (4H, m), 8.05 (1H, s), 8.44 (1H, s)

Preparation 11

To a suspension of7β-amino-3-[1-formyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate) (6.5 g) in methanol (38 ml) was added concentratedhydrochloric acid (3.3 ml). The mixture was stirred at room temperaturefor 2 hours. The reaction mixture was added dropwise ethyl acetate (330ml). The resultant powder was collected by filtration, washed withdiisopropyl ether and dried over phosphorus pentoxide in vacuo to give7β-amino-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatetrihydrochloride (3.35 g).

NMR (D₂ O, δ): 3.37 (1H, d, J=18 Hz), 3.63 (1H, d, J=18 Hz), 3.93-4.47(4H, m), 5.12 (2H, s), 5.14 (1H, d, J=5 Hz), 5.30 (1H, d, J=5 Hz), 5.86(1H, d, J=2 Hz), 7.92 (1H, d, J=2 Hz)

Preparation 12

The following compounds were obtained according to a similar manner tothat of Preparation 11.

(1)7β-Amino-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatetrihydrochloride

IR (Nujol): 3350, 1780, 1700, 1620 cm⁻¹ NMR (DMSO-d₆, δ): 1.87-2.17 (2H,m), 3.27 (2H, br s), 3.36-3.55 (2H, m), 3.85-4.17 (2H, m), 5.23 (2H, brs), 5.29 (2H, br s), 5.76 (1H, d, J=3 Hz), 8.08 (1H, d, J=3 Hz)

(2)7β-Amino-3-[2,3-dihydro-7-methyl-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatetrihydrochloride

NMR (D₂ O-NaHCO₃, δ): 1.59 (3H, s), 3.23, 3.50 (2H, ABq, J=18 Hz, 24Hz), 3.93-4.30 (4H, m), 4.80-5.27 (4H, m), 7.73 (1H, s)

(3)7β-Amino-3-[7-methylthio-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatetrihydrochloride

IR (Nujol): 1785, 1710, 1595 cm⁻¹ NMR (D₂ O-NaHCO₃, δ): 2.31 (3H, s),3.23, 3.53 (2H, ABq, J=18 Hz, 26 Hz), 3.93-4.40 (4H, m), 4.77-5.20 (2H,m), 4.99 (1H, d, J=5 Hz), 8.02 (1H, s)

Preparation 13

5-Aminopyrazole (10 g) and 1,3-dibromopropane (13.4 ml) were added to1,4-dioxane (20 ml) under stirring at ambient temperature. Triethylamine(40.1 ml) was added thereto. The mixture was refluxed under stirring for4 hours. The reaction mixture was cooled to 0°-5° C. in an ice-bath andstirred for 30 minutes. An insoluble material was filtered off, and thefiltrate was evaporated under reduced pressure to give4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (5.1 g).

IR (Nujol): 3220, 1570, 1460 cm⁻¹

Preparation 14

(1) The following compound was obtained according to a similar manner tothat of Preparation 13.

6-Hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine

IR (Nujol): 3350, 3110, 1600, 1460, 1380 cm⁻¹ NMR (DMSO-d₆, δ):2.90-3.30 (2H, m), 3.60-3.80 (1H, m), 4.00-4.20 (2H, m), 5.15 (1H, d,J=1.9 Hz), 5.23 (1H, d, J=3.8 Hz), 5.93 (1H, s), 7.05 (1H, d, J=1.9 Hz)

(2) The following compound was obtained by reacting6-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine according to asimilar manner to that of Preparation 2(2).

4-Formyl-6-formyloxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine

NMR (CDCl₃,δ): 3.30-4.80 (4H, m), 5.50-5.80 (1H, m), 6.01 and 6.67 (eachd, 1H, J=3 Hz), 7.41 (1H, d, J=3 Hz), 7.96 (1H, s), 8.12 and 8.72 (1H,each s)

Preparation 15

(1) To a solution of1-methoxycarbonylmethyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (27 g) inethanol (135 ml) was added 28% ammonium solution (100 ml). The mixturewas stirred overnight at room temperature. The insoluble material wasfiltered off and the filtrate was evaporated to precipitate thecrystals. The crystals were collected by filtration to give1-carbamoylmethyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (6 g).

NMR (DMSO-d₆, δ): 3.06 (2H, s), 3.65-3.91 (2H, m), 3.91-4.21 (2H, m),5.28 (1H, d, J=2 Hz), 7.16 (1H, d, J=2 Hz), 6.87-7.67 (2H, br)

(2) To a suspension of lithium aluminum hydride (2.84 g) intetrahydrofuran (70 ml) was added dropwise a solution of1-carbamoylmethyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (6.2 g) intetrahydrofuran (30 ml) at room temperature. The mixture was refluxedfor 4 hours and cooled with ice-bath. Sodium fluoride (12.5 g) and water(4 ml) were added to the mixture under cooling. The insoluble materialwas filtered off and the filtrate was evaporated to give1-(2-aminoethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (4.2 g).

NMR (DMSO-d₆, δ): 2.42-3.20 (4H, m), 3.40-4.20 (4H, m), 5.25 (1H, s),7.14 (1H, s)

(3) A mixture of acetic anhydride (4.96 ml) and formic acid (2.51 ml)was stirred for 45 minutes at room temperature. The mixture was cooledto 5° C., and 1-(2-aminoethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazole(4.0 g) was added to the mixture. The mixture was stirred for an hourunder ice-cooling. The reaction mixture was evaporated and the residuewas subjected to column chromatography on silica gel using a mixture ofchloroform and methanol (9:1) as an eluent. Fractions containing theobject compound were combined and evaporated to give1-(2-formamidoethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (2.6 g) ascrystals.

NMR (DMSO-d₆, δ): 2.80-3.50 (4H, m), 3.58-3.87 (2H, m), 3.87-4.7 (2H,m), 5.29 (1H, d, J=2 Hz), 7.18 (1H, d, J=2 Hz), 8.03 (1H, s)

Preparation 16

(1) To a mixture of 3-dimethylamino-2-methylthioacrylonitrile (5 g) and2-hydrazinoethanol (2.68 g) in ethanol (50 ml) was added conc.hydrochloric acid (2.93 ml) under ice-cooling. The mixture was refluxedfor 3 hours. The reaction mixture was evaporated to remove the solvent.The residue was adjusted to pH 7 with a saturated aqueous solution ofsodium bicarbonate and extracted with a mixture of tetrahydrofuran andethyl acetate. The organic layer was dried over magnesium sulfate. Thesolvent was removed in vacuo and the residue was subjected to columnchromatography on silica gel using ethyl acetate as an eluent. Fractionscontaining the object compound were combined and evaporated to give1-(2-hydroxyethyl)-4-methylthio-5-aminopyrazole (2.4 g).

IR (Nujol): 3400, 1620, 1540, 1515, 1460 cm⁻¹ NMR (DMSO-d₆, δ): 2.01(3H, s), 3.61 (2H, t, J=5 Hz), 3.83 (2H, t, J=5 Hz), 4.81 (1H, t, J=5Hz), 5.19 (2H, br s), 7.07 (1H, s)

(2) The following compound was obtained according to a similar manner tothat of Preparation 1(1).

1-(2-Hydroxyethyl)-4-methylthio-5-formamidopyrazole

NMR (DMSO-d₆, δ): 2.21, 2.24 (total 3H, each s), 3.63-3.69 (2H, m),3.95, 4.04 (total 2H, each t, J=6 Hz), 7.55, 7.60 (total 1H, each s),8.17, 8.31 (total 1H, each s)

(3) The following compound was obtained according to a similar manner tothat of Preparation 1(2).

1-(2-Methylsulfonyloxyethyl)-4-methylthio-5-formamidopyrazole

NMR (DMSO-d₆, δ): 2.22, 2.24 (total 3H, each s), 3.02, 3.07 (total 3H,each s), 4.24, 4.34 (total 2H, each t, J=5 Hz), 4.50 (2H, t, J=5 Hz),7.63 (1H, s), 8.33 (1H, s), 10.1 (1H, s)

(4) The following compound was obtained according to a similar manner tothat of Preparation 1(3).

1-Formyl-7-methylthio-2,3-dihydro-1H-imidazo[1,2-b]pyrazole

IR (Nujol): 1665, 1560, 1510 cm⁻¹ NMR (DMSO-d₆, δ): 2.25, 4.13-4.47 (4H,m), 7.39 (1H, s), 9.03 (1H, s)

Preparation 17

The following compound was obtained by reacting7β-amino-3-(4-formyl-6-formyloxy-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatebis(trifluoroacetate) according to a similar manner to that ofPreparation 11.

7β-Amino-3-(6-hydroxy-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatetrihydrochloride

IR (Nujol): 3250, 1780, 1620, 1230 cm⁻¹ NMR (DMSO-d₆, δ): 3.40 (2H, brs), 3.20 (1H, m), 3.66 (2H, m), 4.1-4.6 (2H, m), 5.16 (2H, m), 5.23 (2H,s), 5.85 (1H, d, J=3 Hz), 8.60 (1H, d, J=3 Hz)

Preparation 18

A solution of7β-amino-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatetrihydrochloride (87 g) in water (348 ml) was subjected to columnchromatography on HP-20 (609 ml), and the elution was carried out withwater. The fractions containing the objective compound were combined andisopropyl alcohol (3 l) was added dropwise thereto under ice-cooling.The resulting precipitate was collected by filtration to give7β-amino-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatehydrochloride (48.32 g) as crystals.

IR (Nujol): 1780, 1640, 1590 cm⁻¹ NMR (D₂ O, δ): 3.35 and 3.62 (2H, ABq,J=17 Hz), 3.98-4.45 (4H, m), 5.07 (2H, s), 5.16 (1H, d, J=5 Hz), 5.29(1H, d, J=5 Hz), 5.86 (1H, d, J=3 Hz), 7.92 (1H, d, J=3 Hz)

Preparation 19

The following compound was obtained according to a similar manner tothat of Preparation 18.

7β-Amino-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatehydrochloride (crystal)

IR (Nujol): 1790, 1640, 1600 cm⁻¹ NMR (D₂ O, δ): 1.92-2.22 (2H, m),3.11-3.53 (4H, m), 3.95-4.13 (2H, m), 5.06 and 5.21 (2H, ABq, J=15 Hz),5.11 (1H, d, J=5 Hz), 5.22 (1H, d, J=5 Hz), 5.82 (1H, d, J=3 Hz), 7.74(1H, d, J=3 Hz)

Example 1

To a solution of7β-amino-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatetrihydrochloride (0.7 g), N-(trimethylsilyl)acetamide (2.13 g) andmethylene chloride (14 ml) were added2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)aceticmethanesulfonic anhydride (syn isomer) (0.57 g) under ice-cooling. Themixture was stirred at room temperature for 2 hours. The reactionmixture was poured into water (10 ml) and adjusted to pH 6 with asaturated aqueous solution of sodium bicarbonate. The separated aqueouslayer was adjusted to pH 2.5 with 1N hydrochloric acid and the insolublematerial was filtered off. The aqueous solution was subjected to columnchromatography on "Diaion HP-20" (Trademark: manufactured by MitsubishiChemical Industries) using 5% aqueous isopropyl alcohol as an eluent.Fractions containing the object compound were combined and evaporated invacuo to remove isopropyl alcohol. The residue was lyophilized to give7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer) (0.39 g).

IR (Nujol): 3300, 1770, 1670, 1600, 1520 cm⁻¹ NMR (D₂ O-NaHCO₃, δ): 1.53(6H, s), 3.21 (1H, d, J=18 Hz), 3.50 (1H, d, J=18 Hz), 3.93-4.35 (4H,m), 4.90 (1H, d, J=13 Hz), 5.10 (1H, d, J=13 Hz), 5.22 (1H, d, J=5 Hz),5.70-5.92 (2H, m), 7.89 (1H, d, J=2 Hz)

Example 2

A mixture of N,N-dimethylformamide (0.26 ml), ethyl acetate (0.7 ml) andphosphorus oxychloride (0.3 ml) was stirred for 30 minutes underice-cooling and tetrahydrofuran (6 ml) was added thereto.2-(2-Formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer) (0.64g) was added to the mixture under ice-cooling, and the mixture wasstirred for 1 hour at 3 to 5° C. to produce an activated acid solution.On the other hand,7β-amino-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatetrihydrochloride (1.2 g) was dissolved in a solution ofN-trimethylsilylacetamide (3.66 g) in methylene chloride (25 ml). To thesolution was added the above activated acid solution at -20° C. and themixture was stirred at -10° to 0° C. for 2 hours. The reaction mixturewas poured into ethyl acetate (25 ml) and the resultant powder wascollected by filtration and washed with diisopropyl ether and dried overmagnesium sulfate in vacuo to give7β-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer) (3.4 g).

Example 3

To a solution of7β-amino-3-[1-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate) (1 g), N-(trimethylsilyl)acetamide (2.45 g) andmethylene chloride (20 ml) was added2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetic methanesulfonic anhydride (syn isomer) (0.66 g) underice-cooling. The mixture was stirred at 10° C. for 2 hours. The reactionmixture was poured into ethyl acetate (200 ml). The resultant powder wascollected by filtration and dissolved in water, and the solution wasadjusted to pH 2.5 with a saturated sodium bicarbonate solution. Thesolution was subjected to column chromatography on HP-20 using 5%aqueous isopropyl alcohol as an eluent. Fractions containing the objectcompound were combined and evaporated to remove isopropyl alcohol andthe residue was lyophilized to give7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[1-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer) (0.27 g).

IR (Nujol): 3250, 1770, 1670 cm⁻¹ NMR (D₂ O-NaHCO₃, δ): 1.57 (6H, s),2.98 (3H, s), 3.21, 3.50 (2H, ABq, J=18 Hz, 26 Hz), 3.83-4.40 (4H, m),4.80-5.10 (2H, m), 5.23 (1H, d, J=5 Hz), 5.83 (1H, d, J=5 Hz), 5.83(1H,d, J=3 Hz), 7.90 (1H, d, J=3 Hz)

Example 4

To a solution of7β-amino-3-(5-oxo-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatebis(trifluoroacetate) (1.5 g) in a mixture of tetrahydrofuran (40 ml)and water (20 ml) was added N,N-dimethylformamide solvate (1.02 g) of1-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl]-1H-benzotriazol-3-oxideat ambient temperature. The mixture was stirred for 4 hours at pH 7. Thesolution was adjusted to pH 2 with 1N hydrochloric acid, washed withethyl acetate five times and evaporated in vacuo to remove ethylacetate. The solution was subjected to column chromatography on HP-20and the elution was carried out with 5% aqueous isopropyl alcohol. Theobjective fraction was collected and lyophilized to give7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(5-oxo-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer) (261 mg).

IR (Nujol): 3300, 1765, 1700, 1660 cm⁻¹ NMR (D₂ O, δ): 3.03 (2H, t, J=7HZ), 3.19 and 3.51 (2H, ABq, J=18 Hz), 3.97 (3H, s), 4.49 (2H, t, J=7Hz), 5.11 and 5.35 (2H, ABq, J=15 Hz), 5.22 (1H, d, J=5 Hz), 5.82 (1H,d, J=5 Hz), 6.17 (1H, d, J=3 Hz), 6.96 (1H, s), 8.03 (1H, d, J=3 Hz)

Example 5

The following compounds were obtained according to similar manners tothose of Examples 1˜4.

(1)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1670, 1600, 1520 cm⁻¹ NMR (D₂ O, δ): 3.21 (1H, d, J=18Hz), 3.50 (1H, d, J=18 Hz), 4.06 (3H, s), 3.87-4.37 (4H, m), 4.90 (1H,d, J=13 Hz), 5.13 (1H, d, J=13 Hz), 5.21 (1H, d, J=5 Hz), 5.82 (1H, d,J=3 Hz), 5.85 (1H, d, J=5 Hz), 7.89 (1H, d, J=3 Hz)

(2)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1770, 1670, 1600, 1520 cm⁻¹ NMR (D₂ O, δ): 3.20 (1H,d, J=18 Hz), 3.50 (1H, d, J=18 Hz), 3.95-4.47 (4H, m), 4.70-4.88 (2H,m), 4.93-5.60 (4H, m), 5.21 (1H, d, J=5 Hz), 5.82 (1H, d, J=3 Hz),5.70-6.35 (2H, m), 7.89 (1H, d, J=3 Hz)

(3)7β-[2-(2-Formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-(4-methyl-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3200, 1765, 1655, 1620 cm⁻¹ NMR (DMSO-d₆, δ): 1.96-2.23 (2H,m), 2.97 (3H, m), 3.13-3.44 (4H, m), 3.85 (3H, s), 3.88-4.10 (2H, m),5.18 (1H, d, J=5 Hz), 5.20 (2H, br s), 6.12 (1H, d, J=3 Hz), 7.33 (1H,s), 8.08 (1H, d, J=3 Hz), 8.43 (1H, s), 9.60 (1H, d, J=8 Hz)

(4)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4-methyl-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1760, 1660, 1620 cm⁻¹ NMR (D₂ O+NaHCO₃, δ): 1.54 (6H,s), 2.01-2.33 (2H, m), 3.00 (3H, s), 3.14-3.47 (4H, m), 3.88-4.15 (2H,m), 4.88 and 5.19 (2H, ABq, J=16 Hz), 5.18 (1H, d, J=5 Hz), 5.82 (1H, d,J=5 Hz), 5.88 (1H, d, J=3 Hz), 7.77 (1H, d, J=3 Hz)

(5)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-(4-methyl-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1760, 1670, 1615 cm⁻¹ NMR (D₂ O, δ): 2.03-2.32 (2H,m), 2.97 (3H, s), 3.07-3.28 (4H, m), 3.82-4.18 (2H, m), 4.77 (2H, d, J=6Hz), 5.05-5.47 (4H, m), 5.17 (1H, d, J=5 Hz), 5.83 (1H, d, J=5 Hz),5.84-6.28 (1H, m), 5.87 (1H, d, J=3 Hz), 7.77 (1H, d, J=3 Hz)

(6)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3200, 1760, 1650, 1605 cm⁻¹ NMR (D₂ O, δ): 1.93-2.33 (2H,m), 3.05-3.49 (4H, m), 3.92-4.18 (2H, m), 4.08 (3H, s), 4.85 and 5.23(2H, ABq, J=15 Hz), 5.18 (1H, d, J=5 Hz), 5.82 (1H, d, J=3 HZ), 5.84(1H, d, J=5 HZ), 7.73 (1H, d, J=3 Hz)

(7)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1760, 1660, 1600 cm⁻¹ NMR (D₂ O, δ): 1.93-2.32 (2H,m), 3.02-3.48 (4H, m), 3.88-4.18 (2H, m), 4.76 (2H, d, J=6 Hz),4.94-5.44 (4H, m), 5.18 (1H, d, J=5 Hz), 5.78 (1H, d, J=3 Hz), 5.82 (1H,d, J=5 Hz), 5.83-6.27 (1H, m), 7.83 (1H, d, J=3 Hz)

(8)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1770, 1660, 1615 cm⁻¹ NMR (D₂ O, δ): 1.55 (6H, s),1.92-2.28 (2H, m), 3.13-3.44 (4H, m), 3.96-4.18 (2H, m), 4.88 and 5.22(2H, ABq, J=15 Hz), 5.22 (1H, d, J=5 Hz), 5.82 (1H, d, J=5 Hz), 5.83(1H, d, J=3 Hz), 7.74 (1H, d, J=3 Hz)

(9)7β-[2-(2-Formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1775, 1660, 1620 cm⁻¹ NMR (DMSO-d₆, δ): 1.88-2.14 (2H, m),3.18-3.37 (2H, m), 3.34 (2H, m), 3.63-4.16 (2H, m), 3.86 (3H, s), 5.18(1H, d, J=5 Hz), 5.19 (2H, br s), 5.75 (1H, dd, J=8, 5 Hz), 5.82 (1H, d,J=3 Hz), 7.33 (1H, s), 7.99 (1H, d, J=3 Hz), 8.43 (1H, s), 9.59 (1H, d,J=8 Hz)

(10)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4-formyl-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1680, 1600 cm⁻¹ NMR (D₂ O+NaHCO₃, δ): 1.65 (6H, s),2.18-2.62 (2H, m), 3.33 and 3.63 (2H, ABq, J=18 Hz), 3.85-4.17 (2H, m),4.36-4.53 (2H, m), 5.24 and 5.55 (2H, ABq, J=15 Hz), 5.34 (1H, d, J=5Hz), 5.96 (1H, d, J=5 Hz), 6.83 and 7.23 (each 1H, d, J=3 Hz), 8.24 (1H,d, J=3 Hz), 8.46 (1H, s), 8.98 (1H, s)

(11)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(5-oxo-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]-pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1765, 1700, 1660, 1590 cm ⁻¹ NMR (D₂ O, δ): 3.03 (2H,t, J=8 Hz), 3.17 and 3.50 (2H, ABq, J=18 Hz), 4.07 (3H, s), 4.50 (2H, t,J=8 Hz), 5.23 (1H, d, J=5 Hz), 5.24 (2H, br s), 5.84 (1H, d, J=5 Hz),6.17 (1H, d, J=3 Hz), 8.04 (1H, d, J=3 Hz)

(12)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-(5-oxo-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1760, 1700, 1670, 1590 cm⁻¹ NMR (D₂ O, δ): 3.00 (2H,t, J=8 Hz), 3.16 and 3.48 (2H, ABq, J=18 Hz), 4.48 (2H, t, J=8 Hz), 4.78(2H, d, J=6 Hz), 5.23 (1H, d, J=5 Hz), 5.21-5.44 (4H, m), 5.85 (1H, d,J=5 Hz), 6.15 (1H, d, J=3 Hz), 5.90-6.21 (1H, m), 8.02 (1H, d, J=3 Hz)

(13)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(5-oxo-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1765, 1680, 1590 cm⁻¹ NMR (D₂ O+NaHCO₃, δ): 1.56 (6H,s), 3.09 (2H, t, J=8 Hz), 3.19 and 3.51 (2H, ABq, J=18 Hz), 4.56 (2H, t,J=8 Hz), 5.23 (1H, d, J=5 Hz), 5.26 (2H, br s), 5.84 (1H, d, J=5 Hz),6.24 (1H, d, J=3 Hz), 8.08 (1H, d, J=3 Hz)

(14)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1methylethoxyimino)acetamido]-3-[1-(2-hydroxyethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1770, 1670, 1500 cm⁻¹ NMR (D₂ O+NaHCO₃, δ): 1.52 (6H,s), 3.25-3.57 (4H, m), 3.67-3.90 (2H, m), 3.97-4.47 (4H, m), 4.87-5.17(2H, m), 5.27 (1H, d, J=5 Hz), 5.8-6.02 (2H, m), 8.01 (1H, d, J=3 Hz)

(15)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[1-(2-hydroxyethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1760, 1670, 1610 cm⁻¹ NMR (D₂ O, δ): 3.27-3.60 (4H,m), 3.70-3.97 (2H, m), 3.97-4.60 (4H, m), 4.77-5.60 (7H, m), 5.80-6.03(2H, m), 5.97-6.40 (1H, m), 8.03 (1H, d, J=3 Hz)

(16)7β-[2-(2-Formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-[1-(2-hydroxyethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

(17)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[7-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3200-3300, 1770, 1660, 1600 cm⁻¹ NMR (DMSO-d₆, δ): 1.54 (6H,s), 1.73 (3H, s), 3.20, 3.50 (2H, ABq, J=18 Hz, 26 Hz), 3.97-4.30 (4H,m), 4.80-5.0 (2H, m), 5.22 (1H, d, J=5 Hz), 5.82 (1H, d, J=5 Hz), 7.73(1H, s)

(18)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[7-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3200-3300, 1760, 1670, 1610 cm⁻¹ NMR (D₂ O, δ): 1.93 (3H,s), 3.18, 3.47 (2H, ABq, J=18 Hz, 27 Hz), 3.90-4.40 (4H, m), 4.7-5.50(7H, m), 5.83 (1H, d, J=5 Hz), 5.83-6.27 (1H, m), 7.71 (1H, s)

(19)7β-[2-(2-Formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-[7-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

(20)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[1-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1760, 1670, 1600 cm⁻¹ NMR (D₂ O+NaHCO₃, δ): 2.97 (3H, s),3.20, 3.50 (2H, ABq, J=18 Hz, 27 Hz), 3.78-4.43 (4H, m), 4.67-5.50 (6H,m), 5.22 (1H, d, J=5 Hz), 5.85 (1H, d, J=5 Hz), 5.87 (1H, d, J=3 Hz),5.80-6.30 (1H, m), 7.90 (1H, d, J=3 Hz)

(21)7β-[2-(2-Formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-[1-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

(22)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(6-hydroxy-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1770, 1620, 1160 cm⁻¹ NMR (D₂ O, δ): 1.60 (6H, s),3.13 (1H, d, J=18 Hz), 3.53 (1H, d, J=18 Hz), 3.23 (1H, m), 3.40 (2H,m), 4.15 (2H, m), 5.00 (2H, s), 5.13 (1H, d, J=6 Hz), 5.83 (1H, d, J=6Hz), 5.87 (1H, d, J=3 Hz), 7.80 and 7.84 (each d, 1H, J=3 Hz)

(23)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(6-hydroxy-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]-pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1770, 1620, 1040 cm⁻¹ NMR (D₂ O, δ): 3.13 (1H, d, J=18Hz), 3.24 (1H, m), 3.42 (2H, m), 3.53 (1H, d, J=18 Hz), 4.00 (3H, s),4.16 (2H, m), 5.01 (2H, s), 5.13 and 5.18 (1H, each d, J=6 Hz), 5.80(1H, d, J=6 Hz), 5.87 (1H, d, J=3 Hz), 6.96 (1H, s), 7.81 and 7.83 (1H,each d, J=3 Hz)

(24)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(6-hydroxy-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1760, 1620, 1040 cm⁻¹ NMR (D₂ O, δ): 3.13 (1H, d, J=18Hz), 3.24 (1H, m), 3.42 (2H, m), 3.53 (1H, d, J=18 Hz), 4.06 (3H, s),4.15 (2H, m), 5.10 (2H, s), 5.15 and 5.17 (1H, each d, J=6 Hz), 5.81(1H, d, J=6 Hz), 5.86 (1H, d, J=3 Hz), 7.80 and 7.83 (1H, each d, J=3Hz)

(25)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1760, 1660, 1610 cm⁻¹ NMR (D₂ O, δ): 1.33 (3H, t, J=7 Hz),1.91-2.28 (2H, m), 3.03-3.48 (4H, m), 3.92-4.18 (2H, m), 4.33 (2H, q,J=7 Hz), 4.86 and 5.23 (2H, ABq, J=16 Hz), 5.20 (1H, d, J=5 Hz), 5.79(1H, d, J=3 Hz), 5.83 (1H, d, J=5 Hz), 7.84 (1H, d, J=3 Hz)

(26)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[7-methylthio-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1670, 1660, 1620, 1590 cm⁻¹ NMR (D₂ O-NaHCO₃, δ): 1.53 (6H,s), 2.29 (3H, s), 3.21, 3.52 (2H, ABq, J=18 Hz, 26 Hz), 3.93-4.50 (4H,m), 4.88, 5.10 (2H, ABq, J=16 Hz, 20 Hz), 5.22 (1H, d, J=5 Hz), 5.82(1H, d, J=5 Hz), 8.0 (1H, s)

(27)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[7-methylthio-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1670, 1600, 1520 cm⁻¹ NMR (D₂ O-NaHCO₃, δ): 2.28 (3H,s), 3.20, 3.51 (2H, ABq, J=18 Hz, 26 Hz), 3.97 (3H, s), 4.03-4.47 (4H,m), 4.90, 5.05 (2H, ABq, J=10 Hz, 14 Hz), 5.20 (1H, d, J=5 Hz), 5.79(1H, d, J=5 Hz), 6.95 (1H, s), 7.98 (1H, s)

(28)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[7-methylthio-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1660, 1600, 1525 cm⁻¹ NMR (D₂ O-NaHCO₃, δ): 1.33 (3H,t, J=7 Hz), 2.30 (3H, s), 3.22, 3.52 (2H, ABq, J=18 Hz, 26 Hz),3.92-4.53 (6H, m), 4.87-5.12 (2H, m), 5.23 (1H, d, J=5 Hz), 5.84 (1H, d,J=5 Hz), 8.0 (1H, s)

(29)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1670, 1520 cm⁻¹ NMR (D₂ O-NaHCO₃, δ): 1.34 (3H, t, J=7Hz), 3.22, 3.52 (2H, ABq, J=18 Hz, 26 Hz), 3.90-4.50 (4H, m), 4.90, 5.16(2H, ABq, J=16 Hz, 24 Hz), 5.23 (1H, d, J=5 Hz), 5.82 (1H, d, J=3 Hz),5.84 (1H, d, J=5 Hz), 7.90 (1H, d, J=3 Hz)

(30)7β-[2-(2-Aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1660, 1600, 1520 cm⁻¹ NMR (D₂ O-NaHCO₃, δ): 3.21, 3.51(2H, ABq, J=18 Hz, 26 Hz), 3.90-4.53 (4H, m), 4.92, 5.14 (2H, ABq, J=16Hz, 20 Hz), 5.23 (1H, d, J=5 Hz), 4.92-5.56 (4H, m), 5.82 (1H, d, J=5Hz), 5.83 (1H, d, J=2 Hz), 5.70-6.30 (1H, m), 6.97 (1H, s), 7.89 (1H, d,J=2 Hz)

(31)7β-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

NMR (D₂ O, δ): 1.31 (3H, t, J=7 Hz), 3.21, 3.50 (2H, ABq, J=18 Hz, 26Hz), 3.90-4.47 (4H, m), 4.89, 5.13 (2H, ABq, J=16 Hz, 22 Hz), 5.22 (1H,d, J=5 Hz), 5.81 (1H, d, J=3 Hz), 6.93 (1H, s), 7.88 (1H, d, J=3 Hz)

(32)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1670, 1620, 1520 cm⁻¹ NMR (D₂ O, δ): 1.92-2.33 (2H,m), 3.14 and 3.42 (2H, ABq, J=15 Hz), 3.05-3.53 (2H, m), 3.85-4.23 (2H),4.65 (2H, br s), 4.96 and 5.20 (2H, ABq, J=18 Hz), 5.16 (1H, d, J=5 Hz),5.80 (1H, d, J=3 Hz), 5.83 (1H, d, J=5 Hz), 7.75 (1H, d, J=3 Hz)

(33)7β-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1650, 1615, 1525 cm⁻¹ NMR (D₂ O, δ): 1.32 (3H, t, J=7Hz), 1.93-2.33 (2H, m), 3.06-3.53 (4H, m), 3.90-4.18 (2H, m), 4.25 (2H,q, J=7 Hz), 4.86 and 5.20 (2H, ABq, J=18 Hz), 5.21 (1H, d, J=5 Hz), 5.80(1H, d, J=3 Hz), 5.84 (1H, d, J=5 Hz), 6.94 (1H, s), 7.75 (1H, d, J=3Hz)

(34)7β-[2-(2-Aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1765, 1650, 1610, 1520 cm⁻¹ NMR (D₂ O, δ): 1.93-2.35 (2H,m), 3.13 and 3.43 (2H, ABq, J=15 Hz), 3.1014 3.53 (2H, m), 3.93-4.23(2H, m), 4.70 (2H, br s), 4.86 and 5.56 (2H, ABq, J=18 Hz), 5.08-5.50(2H, m), 5.23 (1H, d, J=5 Hz), 5.84 (1H, d, J=3 Hz), 5.86 (1H, d, J=5Hz), 5.85-6.30 (1H, m), 6.98 (1H, s), 7.75 (1H, d, J=3 Hz)

(35)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1660, 1600, 1530 cm⁻¹

(36)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(4-methyl-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3200, 1760, 1660, 1610 cm⁻¹

(37)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1760, 1660, 1610 cm⁻¹

(38)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[1-(2-hydroxyethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1760, 1660, 1610 cm⁻¹

(39)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[7-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3200-3300, 1760, 1660, 1610 cm⁻¹

(40)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[1-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1670, 1610 cm⁻¹

Example 6

To a suspension of7β-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer) (3.4 g) in methanol (17 ml) was added concentratedhydrochloric acid (0.74 ml) at room temperature. The mixture was stirredat ambient temperature for 2 hours. The reaction mixture was poured intoethyl acetate (170 ml). The resultant powder was collected byfiltration, dissolved in water and adjusted to pH 2.5 with a saturatedaqueous solution of sodium bicarbonate. The solution was subjected tocolumn chromatography on "Diaion HP-20" using 5% aqueous isopropylalcohol as an eluent. Fractions containing the object compound werecombined and evaporated to remove isopropyl alcohol. The residue waslyophilized to give7β-[2-(2-aminothiazol-4-yl)-2methoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer) (0.35 g).

IR (Nujol) : 1770, 1660, 1600, 1530 cm⁻¹ NMR (D₂ O, δ): 3.21 (1H, d,J=18 Hz), 3.51 (1H, d, J=18 Hz), 3.98 (3H, s), 3.97-4.47 (4H, m), 4.89(1H, d, J=13 Hz), 5.12 (1H, d, J=13 Hz), 5.21 (1H, d, J=5 Hz), 5.79 (1H,d, J=5 Hz), 5.82 (1H, d, J=3 Hz), 6.96 (1H, s), 7.89 (1H, d, J=3 Hz)

Example 7

The following compounds were obtained according to a similar manner tothat of Example 6.

(1)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]3-(4-methyl-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3200, 1760, 1660, 1610 cm⁻¹ NMR (D₂ O, δ): 1.97-2.32 (2H,m), 3.00 (3H, s), 3.11-3.43 (4H, m), 3.83-4.13 (2H, m), 3.97 (3H, s),4.87 and 5.21 (2H, ABq, J=16 Hz), 5.18 (1H, d, J=5 Hz), 5.79 (1H, d, J=5Hz), 5.88 (1H, d, J=3 Hz), 6.93 (1H, s), 7.76 (1H, d, J=3 Hz)

(2)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1760, 1660, 1610 cm⁻¹ NMR (D₂ O, δ): 1.92-2.28 (2H,m), 3.13-3.49 (4H, m), 3.88-4.24 (2H, m), 3.97 (3H, m), 4.85 and 5.20(2H, ABq, J=15 Hz), 5.17 (1H, d, J=5 Hz), 5.77 (1H, d, J=5 Hz), 5.78(1H, d, J=3 Hz), 6.95 (1H, s), 7.72 (1H, d, J=3 Hz)

(3)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[1(2-hydroxyethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1760, 1660, 1610 cm⁻¹ NMR (D₂ O, δ): 3.30-3.62 (4H,m), 3.73-3.97 (2H, m), 4.07 (3H, s), 4.10-4.43 (4H, m), 4.93, 5.20 (2H,ABq, J=18 Hz, 24 Hz), 5.30 (1H, d, J=5 Hz), 5.90 (1H, d, J=5 Hz), 5.95(1H, d, J=5 Hz), 7.07 (1H, s), 8.03 (1H, d, J=3 Hz)

(4)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[7-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3200-3300, 1760, 1660, 1610 cm⁻¹ NMR (DMSO-d₆, δ): 1.90 (3H,s), 3.10-3.67 (2H, m), 3.83 (3H, s), 3.90-4.60 (4H, m), 4.80-5.17 (3H,m), 5.57 (1H, d, J=5 Hz, 8 Hz), 6.69 (1H, s), 7.16 (2H, br s), 8.03 (1H,s), 9.44 (1H, d, J=8 Hz)

(5)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[1-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1670, 1610 cm⁻¹ NMR (D₂ O, δ): 2.96 (3H, s), 3.20,3.49 (2H, ABq, J=18 Hz, 26 Hz), 3.97 (3H, s), 3.77-4.37 (4H, m), 4.83,5.05 (2H, ABq, J=15 Hz, 21 Hz), 5.19 (1H, d, J=5 Hz), 5.77 (1H, d, J=5Hz), 5.82 (1H, d, J=3 Hz), 6.94 (1H, s), 7.88 (1H, d, J=3 Hz)

Example 8

7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer) (1 g) was dissolved in a mixture of 1N hydrochloric acid(1.64 ml) and water (100 ml) at ambient temperature. The solution waslyophilized to give7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatehydrochloride (syn isomer) (1.04 g).

IR (Nujol): 3270, 1780, 1720, 1675, 1600 cm⁻¹ NMR (D₂ O, δ): 1.61 (6H,s), 3.29 and 3.60 (2H, ABq, J=18 Hz), 3.97-4.44 (4H, m), 5.12 (2H, brs), 5.28 (1H, d, J=5 Hz), 5.85 (1H, d, J=3 Hz), 5.88 (1H, d, J=5 Hz),7.93 (1H, d, J=3 Hz)

Example 9

To a solution of7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer) (1 g) in water (3 ml) was added 2N hydrochloric acid (1 ml)at room temperature. The mixture was stirred at ambient temperature for3 hours, and the resulting precipitate was collected by filtration togive7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatehydrochloride (syn isomer) (202 mg) as crystals.

IR (Nujol): 3400, 3240, 1790, 1710, 1640, 1620, 1600 cm⁻¹ NMR (DMSO-d₆,δ): 1.81-2.28 (2H, m), 3.05-3.52 (4H, m), 3.71-4.32 (2H, m), 4.63 (2H,d, J=6 Hz), 5.00-5.41 (4H, m), 5.17 (1H, d, J=5 Hz), 5.78 (1H, d, J=8, 5Hz), 5.83-6.18 (1H, m), 5.85 (1H, d, J=3 Hz), 8.04 (1H, d, J=3 Hz), 8.17(2H, br s), 8.25 (1H, br s), 9.56 (1H, d, J=8 Hz)

Example 10

7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer) (1 g) was dissolved in a mixture of 1M sulfuric acid (1.64ml) and water 100 ml) at ambient temperature. The solution waslyophilized to give7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatesulfate (syn isomer) (1.19 g).

IR (Nujol): 3250, 1780, 1670, 1600 cm⁻¹ NMR (D₂ O, δ): 1.60 (6H, s),3.26 and 3.60 (2H, ABq, J=18 Hz), 3.95-4.46 (4H, m), 5.10 (2H, br s),5.26 (1H, d, J=5 Hz), 5.85 (1H, d, J=5 Hz), 5.90 (1H, d, J=3 Hz), 5.93(1H, d, J=3 Hz)

Example 11

To a mixture of 2M sulfuric acid (1.52 ml) and ethanol (1.52 ml) wasadded7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer) (0.76 g) at room temperature. The mixture was stirred atambient temperature for 4 hours, and the resulting precipitate wascollected by filtration to give7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatesulfate (syn isomer) (462 mg) as crystals.

IR (Nujol): 3600, 3425, 3180, 1795, 1675, 1640, 1610 cm⁻¹ NMR (DMSO-d₆,δ): 1.81-2.23 (2H, m), 3.12-3.43 (4H, m), 3.83 (3H, s), 3.87-4.26 (2H,m), 4.96-5.36 (2H, m), 5.16 (1H, d, J=5 Hz), 5.78 (1H, dd, J=8, 5 Hz),5.86 (1H, d, J=3 Hz), 6.72 (1H, s), 7.96 (1H, d, J=3 Hz), 9.55 (1H, d,J=8 Hz)

Example 12

To a suspension of7β-(2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer) (0.5 g) in acetonitrile (1 ml) was added 2M sulfuric acid(0.5 ml) at ambient temperature. The mixture was stirred for 30 minutes.The resulting precipitate was collected by filtration to give7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatesulfate (syn isomer) as crystals (380 mg).

IR (Nujol): 3250, 1780, 1750, 1665, 1635, 1610 cm⁻¹ NMR (D₂ O, δ): 1.60(6H, s), 1.93-2.32 (2H, m), 3.10-3.57 (4H, m), 3.92-4.18 (2H, m), 5.15(2H, br s), 5.24 (1H, d, J=5 Hz), 5.82 (1H, d, J=3 Hz), 5.86 (1H, d, J=5Hz), 7.74 (1H, d, J=3 Hz)

Example 13

The following compounds were obtained according to similar manners tothose of Examples 10˜12.

(1)7β-[2-(2-Aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatesulfate (syn isomer) (crystal)

IR (Nujol): 3570, 1780, 1640, 1595, 1535 cm⁻¹ NMR (D₂ O-NaHCO₃, δ):3.27, 3.55 (2H, ABq, J=18 Hz, 26 Hz), 3.98-4.50 (4H, m), 4.94, 5.17 (2H,ABq, J=16 Hz, 20 Hz), 4.97-5.57 (4H, m), 5.22 (1H, d, J=5 Hz), 5.83 (1H,d, J=5 Hz), 5.88 (1H, d, J=3 Hz), 5.77-6.32 (1H, m), 7.07 (1H, s), 7.93(1H, d, J=3 Hz)

(2)7β-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatesulfate (syn isomer) (crystal)

IR (Nujol): 3220, 1780, 1660, 1600, 1580 cm⁻¹ NMR (D₂ O-NaHCO₃, δ): 1.33(3H, t, J=7 Hz), 3.25, 3.53 (2H, ABq, J=18 Hz, 26 Hz), 3.93-4.47 (4H,m), 4.91, 5.15 (2H, ABq, J=16 Hz, 22 Hz), 5.23 (1H, d, J=5 Hz), 5.81(1H, d, J=5 Hz), 5,85 (1H, d, J=3 Hz), 7.03 (1H, s), 7.92 (1H, d, J=3Hz)

(3)7β-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatesulfate (syn isomer) (crystal)

IR (Nujol): 3220, 1785, 1655, 1630, 1560 cm⁻¹ NMR (DMSO-d₆, δ): 1.25(3H, t, J=7 Hz), 1.80-2.25 (2H, m), 3.05-3.50 (4H, m), 3.80-4.30 (4H,m), 5.18 (1H, d, J=5 Hz), 5.80 (1H, d, J=3 Hz), 5.82 (1H, dd, J=5 Hz, 8Hz), 6.72 (1H, s), 9.55 (1H, d, J=8 Hz)

(4)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatesulfate (syn isomer) (crystal)

IR (Nujol): 3200, 1780, 1735, 1650, 1540 cm⁻¹ NMR (D₂ O-NaHCO₃, δ): 1.55(6H, s), 3.20 and 3.50 (2H, ABq, J=18 Hz), 3.97-4.44 (2H, m), 4.92 and5.10 (2H, ABq, J=16 Hz), 5.23 (1H, d, J=5 Hz), 5.82 (1H, d, J=3 Hz),5.83 (1H, d, J=5 Hz), 7.89 (1H, d, J=3 Hz)

Example 14

To a solution of7β-amino-3-[1-(2-formamidoethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatebis(trifluoroacetate) (1.17 g), N-(trimethylsilyl)acetamide (2.5 g) andtetrahydrofuran (25 ml) was added2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-t-butoxycarbonyl-1-methylethoxyimino)aceticmethanesulfonic anhydride (syn isomer) (0.85 g) under ice-cooling. Themixture was stirred at room temperature for 2 hours. The reactionmixture was poured into a mixture of ethyl acetate (25 ml) anddiisopropyl ether (25 ml). The resultant powder was collected byfiltration. To the powder in methanol (10 ml) was added conc.hydrochloric acid (0.67 ml). The mixture was stirred for 2 hours at roomtemperature. The reaction mixture was poured into ethyl acetate (100ml). The resultant powder was collected by filtration. To a solution ofthe powder in a mixture of methylene chloride (3 ml) and anisole (1 ml)was added dropwise trifluoroacetic acid (2 ml) under ice-cooling. Themixture was stirred for 2 hours at room temperature. The reactionmixture was poured into a mixture of diisopropyl ether (30 ml) and ethylacetate (30 ml). The resultant powder was collected by filtration,dissolved in water and adjusted to pH 3 with a saturated aqueoussolution of sodium bicarbonate. The solution was subjected to columnchromatography on HP-20 using 10% aqueous isopropyl alcohol as aneluent. Fractions containing the object compound were combined,evaporated to remove isopropyl alcohol and lyophilized to give7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[1-(2-aminoethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]-methyl-3-cephem-4-carboxylate(syn isomer) (0.23 g).

IR (Nujol): 1775, 1590, 1520 cm⁻¹

NMR (D₂ O-NaHCO₃, δ): 1.55 (9H, s), 3.20, 3.54 (2H, ABq, J=18 Hz, 24Hz), 3.13-3.73 (4H, m), 3.95-4.33 (4H, m), 4.80-5.12 (2H, m), 5.23 (1H,d, J=5 Hz), 5.82 (1H, d, J=5 Hz), 5.94 (1H, d, J=3 Hz), 7.95 (1H, d, J=3Hz)

Example 15

To a suspension of7β-[2-(2-aminothiazol-4-yl)-2-t-butoxycarbonylmethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer) (800 mg) in methylene chloride (2.4 ml) and anisole (0.8ml) was added dropwise trifluoroacetic acid (1.6 ml) at 20° C. Thestirring was continued for 3 hours at the room temperature. The reactionmixture was poured into ethyl acetate. The resulting precipitates werecollected by filtration. The precipitates were dissolved in water (50ml) and the mixture was adjusted to pH 6.5 with a saturated aqueoussolution of sodium bicarbonate. The solution was subjected to columnchromatography on HP-20 using water as an eluent and the objectfractions were adjusted to pH 2.0 with 1N hydrochloric acid. Theresulting solution was subjected to column chromatography on HP-20 using15% aqueous isopropyl alcohol as an eluent and the object fractions werelyophilized to give7β-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer) (300 mg).

IR (Nujol): 1765, 1660, 1610, 1520 cm⁻¹ NMR (D₂ O-NaHCO₃, δ): 1.93-2.28(2H, m), 3.13 and 3.40 (2H, ABq, J=15 Hz), 3.05-3.50 (2H, m), 3.83-4.18(2H, m), 4.55 (2H, br s), 4.88 and 5.12 (2H, ABq, J=18 Hz), 5.16 (1H, d,J=5 Hz), 5.80 (1H, d, J=3 Hz), 5.83 (1H, d, J=5 Hz), 6.95 (1H, s), 7.70(1H, d, J=3 Hz)

Example 16

The following compounds were obtained according to similar manners tothose of Examples 1-4.

(1)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatehydrochloride (syn isomer)

IR (Nujol): 3270, 1780, 1720, 1675, 1600 cm⁻¹

(2)7β-[(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatehydrochloride (syn isomer)

IR (Nujol): 3400, 3240, 1790, 1710, 1640, 1620, 1600 cm⁻¹

(3)7β-[2-(5-Amino-1,2,4,thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3250, 1780, 1670, 1600 cm⁻¹

(4)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3600, 3425, 3180, 1795, 1675, 1640, 1610 cm⁻¹

(5)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3250, 1780, 1750, 1665, 1635, 1610 cm⁻¹

(6)7β-[2-(2-Aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3570, 1780, 1640, 1595, 1535 cm⁻¹

(7)7β-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3220, 1780, 1660, 1600, 1580 cm⁻¹

(8)7β-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3220, 1785, 1655, 1630, 1560 cm⁻¹

(9)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3200, 1780, 1735, 1650, 1540 cm⁻¹

(10)7β-[2-(2-Aminothiazol-4-yl)-2-t-butoxycarbonylmethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

NMR (D₂ O-NaHCO₃, δ): 1.53 (9H, s), 1.98-2.23 (2H, m), 3.08-3.50 (4H,m), 3.85-4.20 (2H, m), 4.61 (2H, br s), 4.18-5.13 (2H, m), 5.21 (1H, d,J=5 Hz), 5.78 (1H, d, J=3 Hz), 5.81 (1H, d, J=5 Hz), 6.88 (1H, s), 7.73(1H, d, J=3 Hz)

(11)7β-[2-(2-Aminothiazol-4-yl)-2-(1-t-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

NMR (D₂ O-NaHCO₃, δ): 1.45 (6H, s), 1.53 (9H, s), 1.95-2.30 (2H, m),3.00-3.53 (4H, m), 3.88-4.23 (2H, m), 4.90-5.20 (2H, m), 5.21 (1H, d,J=5 Hz), 5.78 (1H, d, J=3 Hz), 5.85 (1H, d, J=5 Hz), 6.94 (1H, s), 7.72(1H, d, J=3 Hz)

(12)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[1-(2-aminoethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1775, 1590, 1520 cm⁻¹

(13)7β-[2-(2-Aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1765, 1660, 1610, 1520 cm⁻¹

(14)7β-[2-(2-Aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1660, 1620, 1525 cm⁻¹

Example 17

The following compounds were obtained according to a similar manner tothat of Example 6.

(1)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1770, 1670, 1600, 1520 cm⁻¹

(2)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[1-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1770, 1670 cm⁻¹

(3)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(5-oxo-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1765, 1700, 1660 cm⁻¹

(4)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1670, 1600, 1520 cm⁻¹

(5)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1770, 1670, 1600, 1520 cm⁻¹

(6)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4-methyl-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1760, 1660, 1620 cm⁻¹

(7)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-(4-methyl-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1760, 1670, 1615 cm⁻¹

(8)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3200, 1760, 1650, 1605 cm⁻¹

(9)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1760, 1660, 1600 cm⁻¹

(10)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1770, 1660, 1615 cm⁻¹

(11)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4-formyl-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1680, 1600 cm⁻¹

(12)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(5-oxo-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1765, 1700, 1660, 1590 cm⁻¹

(13)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-(5-oxo-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1760, 1700, 1670, 1590 cm⁻¹

(14)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(5-oxo-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1765, 1680, 1590 cm⁻¹

(15)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamio]-3-[1-(2-hydroxyethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1770, 1670, 1500 cm⁻¹

(16)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[1-(2-hydroxyethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1760, 1670, 1610 cm⁻¹

(17)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[7-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3200-3300, 1770, 1660, 1600 cm⁻¹

(18)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[7-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3200-3300, 1760, 1670, 1610 cm⁻¹

(19)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[1-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1760, 1670, 1600 cm⁻¹

(20)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(6-hydroxy-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1770, 1620, 1160 cm⁻¹

(21)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(6-hydroxy-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1770, 1620, 1040 cm⁻¹

(22)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(6-hydroxy-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1760, 1620, 1040 cm⁻¹

(23)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1760, 1660, 1610 cm⁻¹

(24)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[7-methylthio-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1670, 1660, 1620, 1590 cm⁻¹

(25)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[7-methylthio-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1670, 1600, 1520 cm⁻¹

(26)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[7-methylthio-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1660, 1600, 1525 cm⁻¹

(27)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1670, 1520 cm⁻¹

(28)7β-[2-(2-Aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1660, 1600, 1520 cm⁻¹

(29)7β-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

NMR (D₂ O, δ): 1.31 (3H, t, J=7 Hz), 3.21, 3.50 (2H, ABq, J=18 Hz, 26Hz), 3.90-4.47 (4H, m), 4.89, 5.13 (2H, ABq, J=16 Hz, 22 Hz), 5.22 (1H,d, J=5 Hz), 5.81 (1H, d, J=3 Hz), 6.93 (1H, s), 7.88 (1H, d, J=3 Hz)

(30)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1670, 1620, 1520 cm⁻¹

(31)7β-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1650, 1615, 1525 cm⁻¹

(32)7β-[2-(2-Aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1765, 1650, 1610, 1520 cm⁻¹

(33)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatehydrochloride (syn isomer)

IR (Nujol): 3270, 1780, 1720, 1675, 1600 cm⁻¹

(34)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatehydrochloride (syn isomer)

IR (Nujol): 3400, 3240, 1790, 1710, 1640, 1620, 1600 cm⁻¹

(35)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3250, 1780, 1670, 1600 cm⁻¹

(36)7β-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3600, 3425, 3180, 1795, 1675, 1640, 1610 cm⁻¹

(37)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4,5,6,7-tetahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3250, 1780, 1750, 1665, 1635, 1610 cm⁻¹

(38)7β-[2-(2-Aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3570, 1780, 1640, 1595, 1535 cm⁻¹

(39)7β-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3220, 1780, 1660, 1600, 1580 cm⁻¹

(40)7β-[2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3220, 1785, 1655, 1630, 1560 cm⁻¹

(41)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3200, 1780, 1735, 1650, 1540 cm⁻¹

(42)7β-[2-(2-Aminothiazol-4-yl)-2-t-butoxycarbonylmethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

NMR (D₂ O-NaHCO₃, δ): 1.53 (9H, s), 1.98-2.23 (2H, m), 3.08-3.50 (4H,m), 3.85-4.20 (2H, m), 4.61 (2H, br s), 4.18-5.13 (2H, m), 5.21 (1H, d,J=5 Hz), 5.78 (1H, d, J=3 Hz), 5.81 (1H, d, J=5 Hz), 6.88 (1H, s), 7.73(1H, d, J=3 Hz)

(43)7β-[2-(2-Aminothiazol-4-yl)-2-(1-t-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

NMR (D₂ O-NaHCO₃, δ): 1.45 (6H, s), 1.53 (9H, s), 1.95-2.30 (2H, m),3.00-3.53 (4H, m), 3.88-4.23 (2H, m), 4.90-5.20 (2H, m), 5.21 (1H, d,J=5 Hz), 5.78 (1H, d, J=3 Hz), 5.85 (1H, d, J=5 Hz), 6.94 (1H, s), 7.72(1H, d, J=3 Hz)

(44)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[1-(2-aminoethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1775, 1590, 1520 cm⁻¹

(45)7β-[2-(2-Aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1765, 1660, 1610, 1520 cm⁻¹

(46)7β-[2-(2-Aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1660, 1620, 1525 cm⁻¹

Example 18

The following compounds were obtained according to a similar manner tothat of Example 15.

(1)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1770, 1670, 1600, 1520 cm⁻¹

(2)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[1-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1770, 1670 cm⁻¹

(3)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4-methyl-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3250, 1760, 1660, 1620 cm⁻¹

(4)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1770, 1660, 1615 cm⁻¹

(5)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4-formyl-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1680, 1600 cm⁻¹

(6)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(5-oxo-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1765, 1680, 1590 cm⁻¹

(7)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[1-(2-hydroxyethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1770, 1670, 1500 cm⁻¹

(8)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[7-methyl-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3200-3300, 1770, 1660, 1600 cm⁻¹

(9)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetimido]-3-(6-hydroxy-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 3300, 1770, 1620, 1160 cm⁻¹

(10)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[7-methylthio-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1670, 1660, 1620, 1590 cm⁻¹

(11)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1670, 1620, 1520 cm⁻¹

(12)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]Pyrazolio)]methyl-3-cephem-4-carboxylatehydrochloride (syn isomer)

IR (Nujol): 3270, 1780, 1720, 1675, 1600 cm⁻¹

(13)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3250, 1780, 1670, 1600 cm⁻¹

(14)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3250, 1780, 1750, 1665, 1635, 1610 cm⁻¹

(15)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatesulfate (syn isomer)

IR (Nujol): 3200, 1780, 1735, 1650, 1540 cm⁻¹

(16)7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[1-(2-aminoethyl)-2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1775, 1590, 1520 cm⁻¹

(17)7β-[2-(2-Aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate(syn isomer)

IR (Nujol): 1770, 1660, 1620, 1525 cm⁻¹ NMR (D₂ O-NaHCO₃, δ): 1.52 (6H,s), 1.90-2.28 (2H, m), 3.13 and 3.40 (2H, ABq, J=18 Hz), 3.13-3.45 (2H,m), 3.80-4.18 (2H, m), 4.90 and 5.23 (2H, ABq, J=18 Hz), 5.17 (1H, d,J=5 Hz), 5.81 (1H, d, J=3 Hz), 5.84 (1H, d, J=5 Hz), 6.93 (1H, s), 7.731H, d, J=3 Hz)

What is claimed is:
 1. A compound of the formula: ##STR7## wherein R¹ isamino or a protected amino group, R² is selected from the groupconsisting of lower alkyl, mono (or di or tri) halo(lower)alkyl, loweralkenyl, lower alkynyl, aryl, ar(lower)alkyl, carboxy(lower)alkyl andprotected carboxy(lower) alkyl,R³ is hydrogen, lower alkyl,hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, amino(lower)alkyl,protected amino(lower)alkyl or an imino protective group, R⁴ ishydrogen, lower alkyl or lower alkylthio, A is lower alkylene which maybe substituted with oxo, hydroxy or protected hydroxy and Z is N or CH,or a pharmaceutically acceptable salt thereof.
 2. A compound of claim 1,whereinR² is lower alkyl, lower alkenyl, carboxy(lower)alkyl orprotected carboxy(lower)alkyl and A is lower alkylene which may besubstituted with an oxo, a hydroxy or a protected hydroxy group.
 3. Acompound of claim 2, whereinR² is lower alkyl, lower alkenyl,carboxy(lower)alkyl or esterified carboxy(lower)alkyl, R³ is hydrogen,lower alkyl, hydroxy(lower)alkyl, alkanoyloxy(lower)alkyl,amino(lower)alkyl, lower alkanoylamino(lower)alkyl or lower alkanoylgroup and A is lower alkylene which may be substituted with an oxo, ahydroxy or a lower alkanoyloxy group.
 4. A compound of claim 3,whereinR² is lower alkyl, lower alkenyl, carboxy(lower)alkyl or loweralkoxycarbonyl(lower)alkyl, R³ is hydrogen, lower alkyl,hydroxy(lower)alkyl, lower alkanoyloxy(lower)alkyl, amino(lower)alkyl,lower alkanoylamino(lower)alkyl or lower alkanoyl and A is (C₂-C₃)alkylene which may be substituted with an oxo, a hydroxy or analkanoyloxy group.
 5. A compound of claim 4, whereinR³ is hydrogen,lower alkyl, hydroxy(lower)alkyl, amino(lower)alkyl, loweralkanoylamino(lower)alkyl or lower alkanoyl and A is (C₂ -C₃)alkylenewhich may be substituted with an oxo or a hydroxy group.
 6. A compoundof claim 5 whereinR¹ is amino, R² is carboxy(lower)alkyl, R³ ishydrogen, R⁴ is hydrogen, A is ethylene, and Z is N.
 7. A compound ofclaim 6, which is7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer).
 8. A compound of claim 6, which is7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylatesulfate (syn isomer).
 9. A pharmaceutical composition which comprises,as an active ingredient, an effective amount of a compound of claim 1 ora pharmaceutically acceptable salt thereof in admixture with apharmaceutically acceptable carrier.
 10. A method for the treatment ofinfectious diseases which comprises administering an effective amount ofa compound of claim 1 or a pharmaceutically acceptable salt thereof to ahuman or animal.
 11. A compound of claim 4, wherein A is ethylene.
 12. Acompound of claim 11, wherein R³ and R⁴ are each hydrogen.
 13. Acompound of claim 12, wherein R² is lower alkyl, lower alkenyl orcarboxy(lower)alkyl.
 14. A compound of claim 13, wherein R¹ is amino,and R² is lower alkyl.
 15. A compound of claim 14, wherein Z is CH. 16.A compound of claim 15, which is7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio]methyl-3-cephem-4-carboxylate(syn isomer).
 17. A compound of claim 14, wherein Z is N.
 18. A compoundof claim 17, which is7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer).
 19. A compound of claim 17, which is7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[2,3-dihydro-5-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate(syn isomer).